This invention is directed to a fluorophenyl resin compound and its derivatives, to methods of its preparation and to its use in the solid phase synthesis of amides, peptides, hydroxamic acids, amines, urethanes, carbonates, carbamates, sulfonamides and a-substituted carbonyl compounds.
Solid-phase synthetic techniques, in which a reagent is immobilized on a polymeric material which is inert to the reagents and reaction conditions employed, as well as being insoluble in the media used, are important synthetic tools for preparing amides and peptides as well as for effecting various functional group transformations. For solid phase peptide synthesis, a summary of the many techniques may be found in J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, 2nd. Ed., Pierce Chemical Co. (Chicago, Ill., 1984); J. Meienhofer, Hormonal Proteins and Peptides, vol. 2, p. 46, Academic Press (New York), 1973; and E. Atherton and R. C. Sheppard, Solid Phase Peptide Synthesis: A Practical Approach, IRL Press at Oxford University Press (Oxford, 1989). For the use of solid phase methodology in the preparation of non-peptide molecules see Leznoff, C. C., Acc. Chem. Res., 11, 327-333 (1978). For the use of polymeric reagents in functional group transformations see A. Akelah and D. C. Sherrington, Application of Functionalized Polymers in Organic Synthesis, Chem Rev., 81, 557-587 (1981) and W. T. Ford and E. C. Blossey, Polymer Supported Reagents, Polymer supported Catalysts, and Polymer Supported Coupling Reactions, in Preparative Chemistry using Supported Reagents, Pierre Laszlo, ed., Academic Press, Inc., 193-212 (1987). For the use of polymeric reagents in oxidation reactions see J. M. J. Frechet et al., J. Org. Chem., 43, 2618 (1978) and G. Cainelli et al., J. Am. Chem. Soc., 98, 6737 (1976). For the use of polymeric reagents in halogenation reactions see J. M. J. Frechet et al., J. Macromol. Sci. Chem., A-11, 507 (1977) and D. C. Sherrington et al., Eur. Polym. J., 13, 73, (1977). For the use of polymeric reagents in epoxidation reactions see J. M. J. Frechet et al., Macromolecules, 8, 130 (1975) and C. R. Harrison et al., J. Chem. Soc. Chem. Commun., 1009 (1974). For the use of polymeric reagents in acylation reactions see M. B. Shambhu et al., Tet. Lett., 1627 (1973) and M. B., Shambhu et al., J. Chem. Soc. Chem. Commun., 619 (1974). For the use of polymeric reagents in Wittig reactions see S. V. McKinley et al., J. Chem. Soc. Chem. Commun., 134 (1972).
Polymeric reagents also have found widespread use in combinatorial synthesis and for preparing combinatorial libraries. See F. Balkenhohl et al., Angew. Chem. Int. Ed. Engl., 35, 2288-2337 (1996) and L. A. Thompson et al., Chem Rev., 96, 555-600 (1996).
A 4-hydroxy-tetrafluorophenoxy resin compound of formula 
is disclosed by H. Shao et al., in Abstract No.: 072, Development of TFP Resin for Combinatorial Library Synthesis, Division of Organic Chemistry, 213th ACS National Meeting, Apr. 13-17, 1997.
This invention is directed to a fluorophenyl resin compound of formula I 
wherein 
is a solid support;
A is selected from 
L is a chemical bond,
m is 1 to 5;
p is 0, 1 or 2;
B is F, OW or SO2Z;
D is CH or N;
W is hydrogen, tripyrrolidinophosphonium, C(O)V, C(O)Ra, C(O)NRbRc, C(O)ORa, SO2Ra or 
V is Cl or imidazol-1-yl;
Y is O or NR3;
Z is Cl, xe2x80x94OH, ORa or NRaRi;
Ra and Rf are independently aliphatic or aromatic;
Rb and Rc are independently H, aliphatic or aromatic, or Rb and Rc, taken together with the N atom through which they are attached, form an azaheterocyclyl or azaheterocyclenyl;
Ri is CH2Rf;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
R3 is H or lower alkyl;
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and.
R11, and R12 are independently alkyl, heteroaryl, or aryl.
The fluorophenyl resin compounds of this invention possess a unique advantage over other solid-phase synthesis reagents in that the fluorine atom ortho to the B substituent permit the absolute loading of the resin to be determined using 19F NMR. The large chemical shift differences seen in the spectrum due to the different environments of the ortho fluoro atoms depending whether the chemical species is a phenolate anion, a phenol or a phenolate ester, is extremely useful to monitor the extent of loading of reagents on the tetrafluoro polymer (TFP) resin. The progress of reactions performed on the fluorophenyl resin compounds of this invention may also be monitored by 19F NMR, providing a useful analytical method for reaction optimization. This is especially useful in the case of the activated sulfonate esters where there is not a simple diagnostic IR signal to monitor the-reaction.
In another aspect, this invention is directed to a fluorophenyl activated ester resin compound of formula 
wherein
Ra is aliphatic or aromatic; 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl.
In another aspect, this invention is directed to a process for preparing an amide of formula 
wherein
Ra is aliphatic or aromatic; and
Rb and Rc are independently H, aliphatic or aromatic, or Rb and Rc, taken together with the N atom through which they are attached, form an azaheterocyclyl or azaheterocyclenyl,
comprising reacting a fluorophenyl activated ester resin compound of formula 
wherein
Ra is aliphatic or aromatic; 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl
with a compound of formula HNRbRc.
In another aspect, this invention is directed to a process for preparing a fluorophenyl activated ester resin compound of formula 
wherein
Ra is aliphatic or aromatic; 
is a solid support;
A is selected from 
L is a chemical bond,
m is 1 to 5;
D is CH or N;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl, comprising coupling a 4-hydroxyfluorophenyl resin compound of formula 
wherein 
A, R0, R1 and R2 are defined above,
with a carboxylic acid compound of formula RaCO2H, wherein Ra is defined above, optionally in the presence of an activating agent selected from the group consisting of diisopropylcarbodiimide in the presence of 4-dimethylaminopyridine, and bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP(trademark)) in the presence of triethylamine (TEA).
In another aspect, this invention is directed to a process for preparing an amine compound of formula 
wherein
Ra is aliphatic or aromatic;
Rb and Rc are independently H, aliphatic or aromatic, or Rb and Rc, taken together with the N atom through which they are attached, form an azaheterocyclyl or azaheterocyclenyl,
comprising reacting a 4-(oxysulfonyl)fluorophenyl resin compound of formula 
wherein Ra is defined above; 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O; and
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl, with a compound of formula HNRbRc.
In another aspect, this invention is directed to a process for preparing a 4-(oxysulfonyl)fluorophenyl resin compound of formula 
wherein
Ra is aliphatic or aromatic; 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl, comprising reacting a fluorophenyl-4-sulfonyl chloride resin compound of formula 
wherein 
A, R0, R1 and R2 are defined above,
with a hydroxy compound of formula RaOH, wherein Ra is defined above.
In another aspect, this invention is directed to a process for preparing a sulfonamide compound of formula 
wherein
Ra is aliphatic or aromatic; and
Rb and Rc are independently H, aliphatic or aromatic, or Rb and Rc, taken together with the N atom through which they are attached, form an azaheterocyclyl or azaheterocyclenyl,
comprising reacting a 4-(sulfonyloxy)fluorophenyl resin compound of formula 
Ra is aliphatic or aromatic; 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R4, R5, and R6 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl, with an amine compound of formula HNRbRc.
In another aspect, this invention is directed to a process for preparing a 4-(sulfonyloxy)fluorophenyl resin compound of formula 
Ra is aliphatic or aromatic; 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
comprising reacting a 4-hydroxyfluorophenyl resin compound of formula 
wherein 
A, R0, R1 and R2 are defined above,
with a sulfonyl chloride compound of formula RaSO2Cl in the presence of a base.
In another aspect, this invention is directed to a process for preparing a 4-(sulfonyloxy)fluorophenyl resin compound of formula 
Ra is aliphatic or aromatic; 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
comprising coupling a 4-hydroxyfluorophenyl resin compound of formula 
wherein 
A, R0, R1 and R2 are defined above,
with a sulfonic acid compound of formula RaSO3H, wherein Ra is defined above.
In another aspect, this invention is directed to a process for preparing a 4-(sulfonyloxy)fluorophenyl resin compound of formula 
Ra is aliphatic or aromatic; 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
comprising reacting a 4-hydroxyfluorophenyl resin compound of formula 
wherein 
A, R0, R1 and R2 are defined above,
with a sulfonic anhydride compound of formula (RaSO2)2O.
In another aspect, this invention is directed to a process for preparing a compound of formula 
wherein
T is RaOxe2x80x94 or RdReNxe2x80x94
Ra is aliphatic or aromatic; and
Rb, Rc, Rd and Re are independently H, aliphatic or aromatic, or Rb and Rc, taken together with the N atom through which they are attached, form an azaheterocyclyl or azaheterocyclenyl, or Rd and Re taken together with the N atom through which they are attached, form an azaheterocyclyl or azaheterocyclenyl,
comprising reacting a 4-(aminocarbonyloxy)fluorophenyl resin compound of formula 
wherein 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
with an alcohol of formula RaOH, wherein Ra is defined above, or a compound of formula RdReNH, wherein Rd and Re are defined above, in the presence of base.
In another aspect, this invention is directed to a process for preparing a compound of formula 
wherein
U is RfOxe2x80x94 or RbRcNxe2x80x94
Ra and Rf are independently aliphatic or aromatic; and
Rb and Rc are independently H, aliphatic or aromatic, or Rb and Rc, taken together with the N atom through which they are attached, form an azaheterocyclyl or azaheterocyclenyl,
comprising reacting a 4-(oxycarbonyloxy)fluorophenyl resin compound of formula 
wherein
Ra is aliphatic or aromatic; 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
with an alcohol of formula RfOH, wherein Rf is defined above, or a compound of formula RbRcNH, wherein Rb and Rc are defined above, in the presence of base.
In another aspect, this invention is directed to a process for preparing a 4-(aminocarbonyloxy)fluorophenyl resin compound of formula 
wherein 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
Rb and Rc are independently H, aliphatic or aromatic, or Rb and Rc, taken together with the N atom through which they are attached, form an azaheterocyclyl or azaheterocyclenyl,
comprising converting a 4-hydroxyfluorophenyl resin compound of formula 
wherein 
A, R0, R1 and R2 are defined above, to a 4-(carbonyloxy)fluorophenyl resin compound of formula 
wherein V is Cl or imidazol-1-yl; and
reacting the 4-(carbonyloxy)fluorophenyl resin compound of formula 
with a compound of formula RbRcNH, wherein Rb and Rc are defined above, optionally in the presence of base.
In another aspect, this invention is directed to a process for preparing a 4-(aminocarbonyloxy)fluorophenyl resin compound of formula 
wherein 
is a solid support;
A is selected from 
L is a chemical bond, 
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent; or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
Rb and Rc are independently H, aliphatic or aromatic, or Rb and Rc, taken together with the N atom through which they are attached, form an azaheterocyclyl or azaheterocyclenyl,
comprising reacting a 4-hydroxyfluorophenyl resin compound of formula 
wherein 
A, R0, R1 and R2 are defined above,
with a carbamoyl chloride compound of formula 
wherein Rb and Rc are defined above, optionally in the presence of base.
In another aspect, this invention is directed to a process for preparing a 4-(aminocarbonyloxy)fluorophenyl resin compound of formula 
wherein 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
Rb is aliphatic or aromatic,
comprising reacting a 4-hydroxyfluorophenyl resin compound of formula 
wherein 
A, R0, R1 and R2 are defined above, with an isocyanate compound of formula Oxe2x95x90Cxe2x95x90Nxe2x80x94Rb,
wherein Rb is defined above, optionally in the presence of base.
In another aspect, this invention is directed to a process for preparing a disubstituted amine compound of formula 
wherein
Ra is aliphatic or aromatic;
Ri is CH2Rf; and
Rf is aliphatic or aromatic,
comprising reacting an N,N-disubstituted fluorophenyl-4-sulfonamido resin compound of formula 
wherein
Ra and Ri are defined above; 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; with a thiol.
In another aspect, this invention is directed to a process for preparing an N,N-disubstituted fluorophenyl-4-sulfonamido resin compound of formula 
wherein
Ra is aliphatic or aromatic;
Ri is CH2Rf;
Rf is aliphatic or aromatic; 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
comprising reacting a 4-fluorophenyl sulfonyl chloride compound of formula 
wherein 
A, R0, R1 and R2 are defined above, with a compound of formula H2NRa, wherein Ra is defined above, to form a N-substituted 4-(aminosulfonyl)fluorophenyl resin compound of formula 
and converting the N-substituted 4-(aminosulfonyl)fluorophenyl resin compound to the N,N-disubstituted 4-(aminosulfonyl)fluorophenyl resin compound.
In another aspect, this invention is directed to a process for preparing a 4-hydroxyfluorophenyl resin compound of formula 
wherein 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; comprising reacting a 4-fluorofluorophenyl resin compound of formula 
wherein 
A, R0, R1 and R2 are defined above, with hydroxide.
In another aspect, this invention is directed to a process for preparing a 4-fluorofluorophenyl resin compound of formula 
wherein 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
comprising acylating a resin compound of formula 
with a 4-fluorofluorobenzoyl chloride compound of formula 
wherein R0, R1 and R2 are defined above.
In another aspect, this invention is directed to a process for preparing a 4-fluorofluorophenyl resin compound of formula 
wherein 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
R3 is H; and
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
comprising reacting an amino resin of formula 
with a 4-fluorofluorophenylsulfonyl chloride compound of formula 
wherein R0, R1 and R2 are defined above, in the presence of base.
In another aspect, this invention is directed to a process for preparing a 4-hydroxyfluorophenyl resin compound of formula 
wherein 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
R3 is H; and
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
comprising coupling an amino resin of formula 
with a 4-hydroxyfluorophenyl carboxylic acid compound of formula 
wherein R0, R1 and R2 are defined above.
In another aspect, this invention is directed to a process for preparing a fluorophenyl-4-sulfonic acid resin compound of formula 
wherein 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R1 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
comprising reacting a 4-fluorofluorophenyl resin compound of formula 
wherein R0, R1 and R2 are defined above, with an SO3xe2x88x92 equivalent.
In another aspect, this invention is directed to a process for the preparation of a fluorophenyl-4-sulfonyl chloride resin compound of formula 
wherein 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
comprising reacting a fluorophenyl-4-sulfonic acid resin compound of formula 
wherein R0, R1 and R2 are defined above, with an inorganic acid chloride.
In another aspect, this invention is directed to a process for preparing an xcex1-substituted carbonyl compound of formula 
wherein
Ra is aliphatic or aromatic; and
Rg is H, aliphatic or aromatic and
Rh is aliphatic or aromatic,
comprising reacting a fluorophenyl activated ester resin compound of formula 
wherein
Ra is aliphatic or aromatic; 
is a solid support;
A is selected from 
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR3 or O;
R0, R1 and R2 are independently a ring system substituent, or R0 and R1 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R4, R5, R6 and R7 are independently ring system substituents, or R4 and R5 taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; with a carbon nucleophile of formula RgRhCHxe2x88x92.
As used above and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cSolid supportxe2x80x9d means a substrate which is inert to the reagents and reaction conditions described herein, as well as being substantially insoluble in the media used. Representative solid supports include inorganic substrates such as kieselguhr, silica gel, and controlled pore glass; organic polymers including polystyrene, including 1-2% copolystyrene divinyl benzene (gel form) and 20-40% copolystyrene divinyl benzene (macro porous form), polypropylene, polyethylene glycol, polyacrylamide, cellulose, and the like; and composite inorganic/polymeric compositions such as polyacrylamide supported within a matrix of kieselguhr particles. See J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, 2nd. Ed., Pierce Chemical Co. (Chicago, Ill., 1984).
In addition, xe2x80x9csolid supportxe2x80x9d includes a solid support as described above which is affixed to a second inert support such as the pins described in Technical Manual, Multipin(trademark) SPOC, Chiron Technologies (1995) and references therein which comprise a detachable polyethylene- or polyproylene-based head grafted with an amino functionalized methacrylate copolymer and an inert stem.
In addition, xe2x80x9csolid supportxe2x80x9d includes polymeric supports such as the polyethylene glycol supports described by Janda et al., Proc. Natl. Acad. Sci. USA, 92, 6419-6423 (1995) and S. Brenner, WO 95/16918, which are soluble in many solvents but can be precipitated by the addition of a precipitating solvent.
xe2x80x9cPolyfluorophenyl resin compoundxe2x80x9d means a solid support as defined above which is chemically modified as is known in the art to incorporate a plurality of fluorophenyl groups. The fluorophenyl groups are covalently bound directly to the solid support or attached to the solid support by covalent bonds through a linking group. The fluorophenyl resin compounds according to this invention are designated herein as 
wherein A, R, R1, R2 and B are defined herein, and 
denotes a solid support, as defined herein, or the combination of a solid support and a linking group.
xe2x80x9cPolyfluorophenyl groupxe2x80x9d means a group of formula 
wherein A R, R1, R2 and B are defined herein.
xe2x80x9cLinking groupxe2x80x9d and xe2x80x9clinkerxe2x80x9d mean a group through which the fluorophenyl group may be covalently linked to the solid support. The linking group is substantially inert to the reagents and reaction conditions described herein and generally comprises an inert polymeric material such as polyethylene glycol (PEG, also commonly referred to as polyoxyethylene).
xe2x80x9cAmine protecting groupxe2x80x9d means an easily removable group which is known in the art to protect an amino group against undesirable reaction during synthetic procedures and to be selectively removable. The use of N-protecting groups is well known in the art for protecting amino, and other reactive nitrogen containing groups, against undesirable reactions during a synthetic procedure and many such protecting groups are known, See, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), the contents of which are hereby incorporated herein by reference. Preferred N-protecting groups are acyl, including fonnyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl and the like, and acyloxy including methoxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethxoycarbonyl, vinyloxycarbonyl, t-butyloxycarbonyl (BOC), 1,1 -dimethylpropynyloxycarbonyl, benzyloxycarbonyl (CBZ), p-nitrophenylsulfinyl, p-nitrobenzyloxycarbony, 2,4-dichlorobenzyloxycarbonyl, allyloxycarbonyl (Alloc), and the like.
xe2x80x9cCarboxylic acid protecting groupxe2x80x9d and xe2x80x9cacid protecting groupxe2x80x9d mean an easily removable group which is known in the art to protect a carboxylic acid (xe2x80x94CO2H) group against undesirable reaction during synthetic procedures and to be selectively removable. The use of carboxylic acid protecting groups is well known in the art and many such protecting groups are known, See for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), the contents of which are hereby incorporated herein by reference. Examples of carboxylic acid protecting groups include methoxymethyl, methylthiomethyl, tetrahydropyranyl, benzyloxymethyl, substituted and unsubstituted phenacyl, 2,2,2-trichloroethyl, tert-butyl, cinnamyl, substituted and unsubstituted benzyl, trimethylsilyl, allyl, and the like, and amides and hydrazides groups including N,N-dimethyl, 7-nitroindolyl, hydrazide, N-phenylhydrazide, and the like. Especially preferred carboxylic acid protecting groups are tert-butyl and benzyl.
xe2x80x9cCarbon nucleophile,xe2x80x9d as used herein, refers to an electron pair donor resided on a carbon atom.
xe2x80x9cHydroxy protecting groupxe2x80x9d means an easily removable group which is known in the art to protect a hydroxy group against undesirable reaction during synthetic procedures and to be selectively removable. The use of hydroxy protecting groups is well known in the art and many such protecting groups are known, see., for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), incorporated herein by reference. Examples of hydroxy protecting groups include ether groups such as methyl ether; substituted methyl ethers such as methoxymethyl (MOM)ether, methylthiomethyl (MTM) ether, 2-methoxyethoxymethyl (MEM) ether, bis(2-chloroethoxy)methyl ether, tetrahydropyranyl (THP) ether, tetrahydrothiopyranyl ether, 4-methoxytetrahydropyranyl ether, 4-methoxytetrahydrothiopyranyl ether, tetrahydrofuranyl ether, tetrahydrothiofuranyl ether, and the like; substituted ethyl ethers such as 1-ethoxyethyl ether, 1-methyl-1-methoxyethyl ether 2-(phenylselenyl)ethyl ether, t-butyl ether, allyl ether, benzyl ether, o-nitrobenzyl ether, triphenylmethyl ether, xcex1-naphthyldiphenylmethyl ether, p-methoxyphenyldiphenylmethyl ether, 9-(9-phenyl-10-oxo)anthranyl (tritylone) ether, and the like; silyl ethers such as trimethylsilyl (TMS) ether, isopropyldimethylsilyl ether, t-butyldimethylsilyl (TBDMS) ether, t-butyldiphenylsilyl ether, tribenzylsilyl ether, tri-p-xylylsilyl ether, triisopropylsilyl ether, and the like; esters such as formate, acetate, trichloroacetate, phenoxyacetate, isobutyrate, pivaloate, adamantoate, benzoate, 2,4,6-trimethylbenzoate, and the like; and carbonates such as methyl, 2,2,2-trichloroethyl, allyl, p-nitrophenyl, benzyl, p-nitrobenzyl, S-benzyl thiocarbonate, and the like.
xe2x80x9cAmino acidxe2x80x9d means an amino acid selected from the group consisting of natural and unnatural amino acids as defined herein.
xe2x80x9cNatural amino acidxe2x80x9d means an xcex1-amino acid selected from the group consisting of alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid and glutamic acid.
xe2x80x9cUnnatural amino acidxe2x80x9d means an amino acid for which there is no nucleic acid codon. Examples of unnatural amino acids include, for example, the D-isomers of the natural xcex1-amino acids as indicated above; aminobutyric acid (Abu), aminoisobutyric acid (Aib), 3-aminoisobutyric acid (bAib), norvaline (Nva), xcex2-Ala, 2-aminoadipic acid (Aad), 3-aminoadipic acid (bAad), 2-aminobutyric acid (Abu), xcex3-aminobutyric acid (Gaba), 6-aminocaproic acid (Acp), 2,4-diaminobutryic acid (Dbu), xcex1-aminopimelic acid, trimethylsilyl-Ala (TMSA), allo-isoleucine (aIle), norleucine (Nle), tert-Leu, citrulline (Cit), ornithine (Orn), 2,2xe2x80x2-diaminopimelic acid (Dpm), 2,3-diaminopropionic acid (Dpr), xcex1- or xcex2-Nal, cyclohexyl-Ala (Cha), hydroxyproline, sarcosine (Sar), and the like; cyclic amino acids; Nxcex1-alkylated amino acids such as Nxcex1-methylglycine (MeGly), Nxcex1-ethylglycine (EtGly) and Nxcex1-ethylasparagine (EtAsn); and amino acids in which the xcex1-carbon bears two side-chain substituents.
xe2x80x9cEquivalent amino acidxe2x80x9d means an amino acid which may be substituted for another amino acid in the peptides according to the invention without any appreciable loss of function. In making such changes, substitutions of like amino acids is made on the basis of relative similarity of side chain substituents, for example regarding size, charge, hydrophilicity, hydropathicity and hydrophobicity as described herein.
xe2x80x9cPeptidexe2x80x9d and xe2x80x9cpolypeptidexe2x80x9d mean a polymer in which the monomers are natural or unnatural amino acid residues joined together through amide bonds. The term xe2x80x9cpeptide backbonexe2x80x9d means the series of amide bonds through which the amino acid residues are joined. The term xe2x80x9camino acid residuexe2x80x9d means the individual amino acid units incorporated into the peptides or polypeptides.
xe2x80x9cAliphaticxe2x80x9d means a radical derived from a non aromatic Cxe2x80x94H bond by removal of the hydrogen atom. The aliphatic radical may be further substituted by additional aliphatic or aromatic radicals as defined herein. Representative aliphatic groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkenyl, aralkyloxyalkyl, aralkyloxycarbonylalkyl, aralkyl, aralkynyl, aralkyloxyalkenyl, heteroaralkenyl, heteroaralkyl, heteroaralkyloxyalkenyl, heteroaralkyloxyalkyl, heteroaralkynyl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl, fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyl, and the like.
xe2x80x9cAromaticxe2x80x9d means a radical containing one or more groups of atoms in a cyclic array that contains clouds of delocalized xcfx80 electrons above and below the plane of the atoms; furthermore, the xcfx80clouds must contain a total of (4q+2)xcfx80 electrons, where q is any positive integer. xe2x80x9cAromaticxe2x80x9d includes both aryl and heteroaryl rings as defined herein. The aryl or heteroaryl ring may be further substituted by additional aliphatic or aromatic radicals as defined herein. Representative aromatic groups include aryl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl, heteroaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl, fused heterocyclenylheteroaryl, fused heterocyclylheteroaryl, and the like.
xe2x80x9cAcylxe2x80x9d means an Hxe2x80x94COxe2x80x94 or alkyl-COxe2x80x94 group wherein the alkyl group is as herein described. Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
xe2x80x9cAcylaminoxe2x80x9d is an acyl-NHxe2x80x94 group wherein acyl is as defined herein.
xe2x80x9cAlkenoylxe2x80x9d means an alkenyl-COxe2x80x94 group wherein alkenyl is as defined herein.
xe2x80x9cAlkenylxe2x80x9d means a straight or branched aliphatic hydrocarbon group of 2 to about 15 carbon atoms which contains at least one carbon-carbon double bond. Preferred alkenyl groups have 2 to about 12 carbon atoms; more preferred alkenyl groups have 2 to about 4 carbon atoms. The alkenyl group is optionally substituted with one or more alkyl group substituents as defined herein. Representative alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
xe2x80x9cAlkenylenylxe2x80x9d denotes a divalent group derived from a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond. Representative alkenylenyl include xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHxe2x80x94, xe2x80x94C(CH3)xe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94, and the like.
xe2x80x9cAlkenyloxyxe2x80x9d means an alkenyl-Oxe2x80x94 group wherein the alkenyl group is as herein described. Representative alkenyloxy groups include allyloxy or 3-butenyloxy.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-Oxe2x80x94 group wherein the alkyl group is as defined herein. Representative alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, heptoxy, and the like.
xe2x80x9cAlkoxyalkylenylxe2x80x9d means an alkyl-O-alkylenyl-group wherein alkyl and alkylenyl are as defined herein. Representative alkoxyalkylenyl groups include methoxyethyl, ethoxymethyl, n-butoxymethyl and cyclopentylmethyloxyethyl.
xe2x80x9cAlkoxyalkoxyxe2x80x9d means an alkyl-O-alkylenyl-Oxe2x80x94 group. Representative alkoxyalkoxy include methoxymethoxy, methoxyethoxy, ethoxyethoxy, and the like.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an ester group; i.e. an alkyl-Oxe2x80x94COxe2x80x94 group wherein alkyl is as defined herein. Representative alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, t-butyloxycarbonyl, and the like.
xe2x80x9cAlkoxycarbonylalkylenylxe2x80x9d means an alkyl-Oxe2x80x94CO-alkylenyl-group wherein alkyl and alkylenyl are as defined herein. Representative alkoxycarbonylalkyl include methoxycarbonylmethyl, and ethoxycarbonylmethyl, methoxycarbonyl ethyl, and the like.
xe2x80x9cAlkylxe2x80x9d means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. xe2x80x9cLower alkylxe2x80x9d means about 1 to about 4 carbon atoms in the chain which may be straight or branched. The alkyl may be substituted with one or more xe2x80x9calkyl group substituentsxe2x80x9d which may be the same or different, and include halo, cycloalkyl, hydroxy, alkoxy, amino, carbamoyl, acylamino, aroylamino, carboxy, alkoxycarbonyl, aralkyloxycarbonyl, or heteroaralkyloxycarbonyl. Representative alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylethyl, benzyloxycarbonylmethyl, and pyridylmethyloxycarbonylmethyl.
xe2x80x9cAlkylenyxe2x80x9d means a straight or branched bivalent hydrocarbon chain of 1 to about 20 carbon atoms. Alkylenyl may be substituted by one or more alkyl group substituents as defined herein. Preferred alkylenyl groups are the lower alkylenyl groups having 1 to about 4 carbon atoms. Representative alkylenyl groups include methylene, ethylene, and the like.
xe2x80x9cAlkylsulfinylxe2x80x9d means an alkyl-SOxe2x80x94 group wherein the alkyl group is as defined above. Preferred alkylsulfinyl groups are those wherein the alkyl group is lower alkyl.
xe2x80x9cAlkylsulfonylxe2x80x9d means an alkyl-SO2-group wherein the alkyl group is as defined herein. Preferred alkylsulfonyl groups are those wherein the alkyl group is lower alkyl.
xe2x80x9cAlkylsulfonylcarbamoylxe2x80x9d means an alkyl-SO2xe2x80x94NHxe2x80x94COxe2x80x94 group wherein alkyl group is defined herein. Preferred alkylsulfonylcarbamoyl groups are those wherein the alkyl group is lower alkyl.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl-Sxe2x80x94 group wherein the alkyl group is as defined herein. Preferred alkylthio groups are those wherein the alkyl group is lower alkyl. Representative alkylthio groups include methylthio, ethylthio, i-propylthio, heptylthio, and the like.
xe2x80x9cAlkynylxe2x80x9d means a straight or branched aliphatic hydrocarbon group of 2 to about 15 carbon atoms which contains at least one carbon-carbon triple bond. Preferred alkynyl groups have 2 to about 12 carbon atoms. More preferred alkynyl groups contain 2 to about 4 carbon atoms. xe2x80x9cLower alkynylxe2x80x9d means alkynyl of 2 to about 4 carbon atoms. The alkynyl group may be substituted by one or more alkyl group substituents as defined herein. Representative alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl, decynyl, and the like.
xe2x80x9cAlkynylenylxe2x80x9d refers to a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing a carbon-carbon triple bond. Representative alkynylenyl include 
and the like.
xe2x80x9cAlkynyloxyxe2x80x9d means an alkynyl-Oxe2x80x94 group wherein the alkynyl group is defined herein. Representative alkynyloxy groups include propynyloxy, 3-butynyloxy, and the like.
xe2x80x9cAlkynyloxyalkylenylxe2x80x9d means alkyny-O-alkylenyl-group wherein alkynyl and alkylenyl are defined herein.
xe2x80x9cAmidinoxe2x80x9d or xe2x80x9camidinexe2x80x9d means a group of formula 
wherein R8 is selected from hydrogen; R10O2Cxe2x80x94 (wherein R10 is hydrogen, alkyl, aralkyl or heteroaralkyl); R10Oxe2x80x94; R10C(O)xe2x80x94; (wherein R10 is hydrogen, alkyl, aralkyl or heteroaralkyl); cyano; alkyl; nitro; and amino, and R9 is selected from hydrogen; alkyl; aralkyl; and heteroaralkyl.
xe2x80x9cAminoxe2x80x9d means a group of formula Y1Y2Nxe2x80x94 wherein Y1 and Y2 are independently hydrogen; acyl; or alkyl, or Y1 and Y2 taken together with the N through which Y1 and Y2 are linked form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl. Representative amino groups include amino (H2Nxe2x80x94), methylamino, dimethylamino, diethylamino, and the like.
xe2x80x9cAminoalkylenylxe2x80x9d means an amino-alkylenyl-group wherein amino and alkylenyl are defined herein. Representative aminoalkylenyl groups include aminomethyl, aminoethyl, dimethylaminomethyl, and the like.
xe2x80x9cAralkenylxe2x80x9d means an aryl-alkenylenyl-group wherein aryl and alkenylenyl are define herein. Preferred aralkenyls contain a lower alkenyl moiety. A representative aralkenyl group is 2-phenethenyl.
xe2x80x9cAralkyloxyxe2x80x9d means an aralkyl-Oxe2x80x94 group wherein aralkyl is defined herein. Representative aralkoxy groups include benzyloxy, naphth-1-ylmethoxy, naphth-2-ylmethoxy, and the like.
xe2x80x9cAralkyloxyalkylenylxe2x80x9d means an aralkyl-O-alkylenyl-group wherein aralkyl and alkylenyl are defined herein. A representative aralkoxyalkylenyl group is benzyloxyethyl.
xe2x80x9cAralkyloxycarbonylxe2x80x9d means an aralkyl-Oxe2x80x94COxe2x80x94 group wherein aralkyl is defined herein. A representative aralkoxycarbonyl group is benzyloxycarbonyl.
xe2x80x9cAralkyloxycarbonylalkylxe2x80x9d means an aralkoxycarbonyl group attached to the parent molecular moiety through an alkylene. Representative aralkoxycarbonylalkyls include benzyloxycarbonylmethyl, benzyloxycarbonylethyl.
xe2x80x9cAralkylxe2x80x9d means an aryl-alkylenyl-. Preferred aralkyls contain a lower alkyl moiety. Representative aralkyl groups include benzyl, 2-phenethyl, naphthlenemethyl, and the like.
xe2x80x9cAralkyloxyalkenylenylxe2x80x9d means an aralkyl-O-alkenylenyl-group wherein aralkyl and alkenylenyl are defined herein. A representative aralkyloxyalkenylenyl group is 3-benzyloxyallyl.
xe2x80x9cAralkylsulfonylxe2x80x9d means an aralkyl-SO2xe2x80x94 group wherein aralkyl is defined herein.
xe2x80x9cAralkylsulfinylxe2x80x9d means an aralkyl-SOxe2x80x94 group wherein aralkyl is defined herein.
xe2x80x9cAralkylthioxe2x80x9d means an aralkyl-Sxe2x80x94 group wherein aralkyl is defined herein. A representative aralkylthio group is benzylthio.
xe2x80x9cAroylxe2x80x9d means an aryl-COxe2x80x94 group wherein aryl is defined herein. Representative aroyl include benzoyl, naphth-1-oyl and naphth-2-oyl.
xe2x80x9cArylxe2x80x9d means an aromatic monocyclic or multicyclic ring system of 6 to about 14 carbon atoms, preferably of about 6 to about 10 carbon atoms. The aryl is optionally substituted with one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. Representative aryl groups include phenyl and naphthyl.
xe2x80x9cAralkynylxe2x80x9d means an aryl-alkynylenyl-group wherein aryl and alkynylenyl are defined herein. Representative aralkynyl groups include phenylacetylenyl and 3-phenylbut-2-ynyl.
xe2x80x9cAryldiazoxe2x80x9d means an aryl-Nxe2x95x90Nxe2x80x94 group wherein aryl is defined herein. Representative aryldiazo groups include phenyldiazo and naphthyldiazo.
xe2x80x9cArylcarbamoylxe2x80x9d means an aryl-NHCOxe2x80x94 group, wherein aryl is defined herein.
xe2x80x9cCarbamylxe2x80x9d means a group of formula Y1 Y2NCOxe2x80x94 wherein Y1 and Y2 are defined herein. Representative carbamyl groups include carbamyl (H2NCOxe2x80x94), dimethylaminocarbamoyl (Me2NCOxe2x80x94), and the like.
xe2x80x9cFused arylcycloalkenylxe2x80x9d means a radical derived from a fused aryl and cycloalkenyl as defined herein by removal of hydrogen atom from the cycloalkenyl portion. Preferred fused arylcycloalkenyls are those wherein aryl is phenyl and the cycloalkenyl consists of about 5 to about 6 ring atoms. The fused arylcycloalkenyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. Representative fused arylcycloalkenyl include 1,2-dihydronaphthylene, indene, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused cycloalkenylarylxe2x80x9d means a radical derived from a fused arylcycloalkenyl as defined herein by removal of hydrogen atom from the aryl portion. Representative fused cycloalkenylaryl are as described herein for a fused arylcycloalkenyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused arylcycloalkylxe2x80x9d means a radical derived from a fused aryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. Preferred fused arylcycloalkyls are those wherein aryl is phenyl and the cycloalkyl consists of about 5 to about 6 ring atoms. The fused arylcycloalkyl is optionally substituted by one or more ring system-substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. Representative fused arylcycloalkyl includes 1,2,3,4-tetrahydronaphthyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused cycloalkylarylxe2x80x9d means a radical derived from a fused arylcycloalkyl as defined herein by removal of a hydrogen atom from the aryl portion. Representative fused cycloalkylaryl are as described herein for a fused arylcycloalkyl radical, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused arylheterocyclenylxe2x80x9d means a radical derived from a fused aryl and heterocyclenyl as defined herein by removal of a hydrogen atom from the heterocyclenyl portion. Preferred fused arylheterocyclenyls are those wherein aryl is phenyl and the heterocyclenyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl portion of the fused arylheterocyclenyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused arylheterocyclenyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen or sulphur atom of the heterocyclenyl portion of the fused arylheterocyclenyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative fused arylheterocyclenyl include 3H-indolinyl, 1H-2-oxoquinolyl, 2H-1-oxoisoquinolyl, 1,2-dihydroquinolinyl, 3,4-dihydroquinolinyl, 1,2-dihydroisoquinolinyl, 3,4-dihydroisoquinolinyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon or nitrogen atom capable of such.
xe2x80x9cFused heterocyclenylarylxe2x80x9d means a radical derived from a fused arylheterocyclenyl as defined herein by removal of a hydrogen atom from the aryl portion. Representative fused heterocyclenylaryl are as defined herein for a fused arylheterocyclenyl radical, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused arylheterocyclylxe2x80x9d means a radical derived from a fused aryl and heterocyclyl as defined herein by removal of a hydrogen atom from the heterocyclyl portion. Preferred fused arylheterocyclyls are those wherein aryl is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused arylheterocyclyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen or sulphur atom of the heterocyclyl portion of the fused arylheterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative preferred fused arylheterocyl ring systems include indolinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 1H-2,3-dihydroisoindolyl, 2,3-dihydrobenz[f]isoindolyl, 1,2,3,4-tetrahydrobenz[g]isoquinolinyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon or nitrogen atom.
xe2x80x9cFused heterocyclylarylxe2x80x9d means a radical derived from a fused aryiheterocyclyl as defined herein by removal of a hydrogen atom from the heterocyclyl portion. Representative preferred fused heterocyclylaryl ring systems are as described for fused arylheterocyclyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cCarboxyxe2x80x9d means a HO(O)Cxe2x80x94 group (i.e. a carboxylic acid).
xe2x80x9cCarboxyalkylxe2x80x9d means a HO2C-alkylenyl-group wherein alkylenyl is defined herein. Representative carboxyalkyls include carboxymethyl and carboxyethyl.
xe2x80x9cCycloalkyloxyxe2x80x9d means a cycloalkyl-Oxe2x80x94 group wherein cycloalkyl is defined herein. Representative cycloalkyloxy groups include cyclopentyloxy, cyclohexyloxy, and the like.
xe2x80x9cCycloalkylxe2x80x9d means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 6 ring atoms. The cycloalkyl is optionally substituted with one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. Representative monocyclic cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl, and the like. Representative multicyclic cycloalkyl include 1-decalin, norbornyl, adamantyl, and the like.
xe2x80x9cCycloalkenylxe2x80x9d means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkylene rings contain about 5 to about 6 ring atoms. The cycloalkenyl is optionally substituted with one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. Representative monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. A representative multicyclic cycloalkenyl is norbornylenyl.
xe2x80x9cCycloalkylenylxe2x80x9d means a bivalent, saturated carbocyclic group having about 4 to about 8 carbon atoms. Preferred cycloalkylenyl groups include 1,2-, 1,3-, or 1,4-cis or trans-cyclohexanylene.
xe2x80x9cDiazoxe2x80x9d means a bivalent xe2x80x94Nxe2x95x90Nxe2x80x94 radical.
xe2x80x9cChemical bondxe2x80x9d means a direct bond.
xe2x80x9cEthylenylxe2x80x9d means a xe2x80x94CHxe2x95x90CHxe2x80x94 group.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d mean fluoro, chloro, bromo, or iodo.
xe2x80x9cHeteroaralkenylxe2x80x9d means a heteroaryl-alkenylenyl-group wherein heteroaryl and alkenylenyl are defined herein. Preferred heteroaralkenyls contain a lower alkenylene moiety. Representative heteroaralkenyl groups include 4-pyridylvinyl, thienylethenyl, pyridylethenyl, imidazolylethenyl, pyrazinylethenyl, and the like.
xe2x80x9cHeteroaralkylxe2x80x9d means a heteroaryl-alkylenyl-group wherein heteroaryl and alkylenyl are defined herein. Preferred heteroaralkyls contain a lower alkylenyl group. Representative heteroaralkyl groups include thienylmethyl, pyridylmethyl, imidazolylmethyl, pyrazinylmethyl, and the like.
xe2x80x9cHeteroaralkyloxyxe2x80x9d means an heteroaralkyl-Oxe2x80x94 group wherein heteroaralkyl is defined herein. A representative heteroaralkyloxy group is 4-pyridylmethyloxy.
xe2x80x9cHeteroaralkyloxyalkenylxe2x80x9d means a heteroaralkyl-O-alkenylenyl-group wherein heteroaralkyl and alkenylenyl are defined herein. A representative heteroaralkyloxyalkenyl group is 4-pyridylmethyloxyallyl.
xe2x80x9cHeteroaralkyloxyalkylxe2x80x9d means a heteroaralkyl-O-alkylene-group wherein heteroaralkyl and alkylene are defined herein. A representative heteroaralkyloxy group is 4-pyridylmethyloxyethyl.
xe2x80x9cHeteroaralkynylxe2x80x9d means an heteroaryl-alkynylene-group wherein heteroaryl and alkynylene are defined herein. Preferred heteroaralkynyls contain a lower alkynylene moiety. Representative heteroaralkynyl groups include pyrid-3-ylacetylenyl, quinolin-3-ylacetylenyl, 4-pyridylethynyl, and the like.
xe2x80x9cHeteroaroylxe2x80x9d means an means a heteroaryl-COxe2x80x94 group wherein heteroaryl is defined herein. Representative heteroaroyl groups include thiophenoyl, nicotinoyl, pyrrol-2-ylcarbonyl, pyridinoyl, and the like.
xe2x80x9cHeteroarylxe2x80x9d means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred heteroaryls contain about 5 to about 6 ring atoms. The xe2x80x9cheteroarylxe2x80x9d may also be substituted by one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. A nitrogen atom of a heteroaryl may be oxidized to the corresponding N-oxide. Representative heteroaryls include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, or 1,2,4-triazinyl.
xe2x80x9cHeteroaryidiazoxe2x80x9d means an heteroaryl-Nxe2x95x90Nxe2x80x94 group wherein heteroaryl is as defined herein.
xe2x80x9cFused heteroarylcycloalkenylxe2x80x9d means a radical derived from a fused heteroaryl and cycloalkenyl as defined herein by removal of a hydrogen atom from the cycloalkenyl portion. Preferred fused heteroarylcycloalkenyls are those wherein the heteroaryl and the cycloalkenyl each contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused heteroarylcycloalkenyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkenyl is optionally oxidized to the corresponding N-oxide. Representative fused heteroarylcycloalkenyl include 5,6-dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5-dihydro-1H-benzimidazolyl, 4,5-dihydrobenzoxazolyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused cycloalkenylheteroarylxe2x80x9d means a radical derived from a fused heteroarylcycloalkenyl as defined herein by removal of a hydrogen atom from the heteroaryl portion. Representative fused cycloalkenylheteroaryl are as described herein for fused heteroarylcycloalkenyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused heteroarylcycloalkylxe2x80x9d means a radical derived from a fused heteroaryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. Preferred fused heteroarylcycloalkyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the cycloalkyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylcycloalkyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkyl is optionally oxidized to the corresponding N-oxide. Representative fused heteroarylcycloalkyl include 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl, 4,5,6,7-tetrahydro-1H-benzimidazolyl, 4,5,6,7-tetrahydrobenzoxazolyl, 1H-4-oxa-1,5-diazanaphthalen-2-onyl, 1,3-dihydroimidizole-[4,5]-pyridin-2-onyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused cycloalkylheteroarylxe2x80x9d means a radical derived from a fused heteroarylcycloalkyl as defined herein by removal of a hydrogen atom from the heteroaryl portion. Representative fused cycloalkylheteroaryl are as described herein for fused heteroarylcycloalkyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused heteroarylheterocyclenylxe2x80x9d means a radical derived from a fused heteroaryl and heterocyclenyl as defined herein by the removal of a hydrogen atom from the heterocyclenyl portion. Preferred fused heteroarylheterocyclenyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclenyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl or heterocyclenyl means that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylheterocyclenyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylheterocyclenyl is optionally oxidized to the corresponding N-oxide. The nitrogen or sulphur atom of the heterocyclenyl portion of the fused heteroarylheterocyclenyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative fused heteroarylheterocyclenyl include 7,8-dihydro[1,7]naphthyridinyl, 1,2-dihydro[2,7]naphthyridinyl, 6,7-dihydro-3H-imidazo[4,5-c]pyridyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2-dihydro-1,6-naphthyridinyl, 1,2-dihydro-1,7-naphthyridinyl, 1,2-dihydro-1,8-naphthyridinyl, 1,2-dihydro-2,6-naphthyridinyl, and the like, in which the bond to the parent moiety is through a non aromatic carbon or nitrogen atom.
xe2x80x9cFused heterocyclenylheteroarylxe2x80x9d means a radical derived from a fused heteroarylheterocyclenyl as defined herein by the removal of a hydrogen atom from the heteroaryl portion. Representative fused heterocyclenylheteroaryl are as described herein for fused heteroarylheterocyclenyl, except that the bond to the parent moiety is through an aromatic carbon or nitrogen atom.
xe2x80x9cFused heteroarylheterocyclylxe2x80x9d means a radical derived from a fused heteroaryl and heterocyclyl as defined herein, by removal of a hydrogen atom from the heterocyclyl portion. Preferred fused heteroarylheterocyclyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heteroaryl or heterocyclyl portion of the fused heteroarylheterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused heteroarylheterocyclyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of the heteroary portion of the fused heteroarylheterocyclyl is optionally oxidized to the corresponding N-oxide. The nitrogen or sulphur atom of the heterocyclyl portion of the fused heteroarylheterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative fused heteroarylheterocyclyl include 2,3-dihydro-1H pyrrol[3,4-b]quinolin-2-yl, 1,2,3,4-tetrahydrobenz [b][1,7]naphthyridin-2-yl, 1,2,3,4-tetrahydrobenz [b][1,6]naphthyridin-2-yl, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2yl, 1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-2yl 2,3,-dihydro-1H-pyrrolo[3,4-b]indol-2-yl, 1H-2,3,4,5-tetrahydroazepino[3,4-b]indol-2-yl, 1H-2,3,4,5-tetrahydroazepino[4,3-b]indol-3-yl, 1H-2,3,4,5-tetrahydroazepino[4,5-b]indol-2 yl, 5,6,7,8-tetrahydro[1,7]napthyridinyl, 1,2,3,4-tetrhydro[2,7]naphthyridyl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridyl, 2,3-dihydro[1,4]dioxino[2,3-b]pryidyl, 3,4-dihydro-2H-1-oxa[4,6]diazanaphthalenyl, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl, 6,7-dihydro[5,8]diazanaphthalenyl, 1,2,3,4-tetrahydro[1,5]naphthyridinyl, 1,2,3,4-tetrahydro[1,6]naphthyridinyl, 1,2,3,4-tetrahydro[1,7]naphthyridinyl, 1,2,3,4-tetrahydro[1,8]naphthyridinyl, 1,2,3,4-tetrahydro[2,6]naphthyridinyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon or nitrogen atom.
xe2x80x9cFused heterocyclylheteroarylxe2x80x9d means a radical derived from a fused heteroarylheterocyclyl as defined herein, by removal of a hydrogen atom from the heteroaryl portion. Representative fused heterocyclylheteroaryl are as described herein for fused heterarylheterocyclyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cHeteroarylsulphonylcarbamoylxe2x80x9d means a heteroaryl-SO2xe2x80x94NHxe2x80x94COxe2x80x94 group wherein heteroaryl is defined herein.
xe2x80x9cHeterocyclenylxe2x80x9d means a non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur atoms, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclenyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl may be optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen or sulphur atom of the heterocyclenyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative monocyclic azaheterocyclenyl groups include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Representative oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. A representative multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl. Representative monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like
xe2x80x9cHeterocyclylxe2x80x9d means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclyl is optionally substituted by one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. The nitrogen or sulphur atom of the heterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative monocyclic heterocyclyl rings include 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. Representative monocyclic azaheterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl and the like.
xe2x80x9cHeterocyclylalkylxe2x80x9d means a heterocyclyl-alkylene-group wherein heterocyclyl and alkylene are defined herein. Preferred heterocyclylalkyls contain a lower alkylene moiety. A representative heteroaralkyl group is tetrahydropyranylmethyl.
xe2x80x9cHeterocyclylalkyloxyalkylxe2x80x9d means a heterocyclylalkyl-O-alkylene group wherein heterocyclylalkyl and alkylene are defined herein. A representative heterocyclylalkyloxyalkyl group is tetrahydropyranylmethyloxymethyl.
xe2x80x9cHeterocyclyloxyxe2x80x9d means a heterocyclyl-Oxe2x80x94 group wherein heterocyclyl is defined herein.
Representative heterocyclyloxy groups include quinuclidyloxy, pentamethylenesulfideoxy, tetrahydropyranyloxy, tetrahydrothiophenyloxy, pyrrolidinyloxy, tetrahydrofuranyloxy, 7-oxabicyclo[2.2.1 ]heptanyloxy, hydroxytetrahydropyranyloxy, hydroxy-7-oxabicyclo[2.2.1]heptanyloxy, and the like.
xe2x80x9cHydroxyalkylxe2x80x9d means an alkyl group as defined herein substituted with one or more hydroxy groups. Preferred hydroxyalkyls contain lower alkyl. Representative hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
xe2x80x9cN-oxidexe2x80x9d means a 
group.
xe2x80x9cPhenoxyxe2x80x9d means a phenyl-Oxe2x80x94 group wherein the phenyl ring is optionally substituted with one or more ring system substituents as defined herein.
xe2x80x9cPhenylenexe2x80x9d means a -phenyl-group wherein the phenyl ring is optionally substituted with one or more ring system substituents as defined herein.
xe2x80x9cPhenylthioxe2x80x9d means a phenyl-Sxe2x80x94 group wherein the phenyl ring is optionally substituted with one or more ring system substituents as defined herein.
xe2x80x9cPyridyloxyxe2x80x9d means a pyridyl-Oxe2x80x94 group wherein the pyridyl ring is optionally substituted with one or more ring system substituents as defined herein.
xe2x80x9cRing system substituentsxe2x80x9d mean substituents attached to aromatic or non-aromatic ring systems inclusive of hydrogen, alkyl, aralkyl, heteroaryl, aryl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, formyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, nitrile, NO2, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryidiazo, heteroaryldiazo, amidino, amino, aminoalkyl, carbamyl and sulfamyl. When a ring system is saturated or partially saturated, the xe2x80x9cring system substituentxe2x80x9d further comprises methylene (H2Cxe2x95x90), oxo (Oxe2x95x90) and thioxo (Sxe2x95x90). Preferred ring system substituents are hydrogen, CF3, fluoro, alkyl, alkoxy, nitrile or NO2.
xe2x80x9cSulfamylxe2x80x9d means a group of formula Y1Y2NSO2xe2x80x94 wherein Y1 and Y2 are defined herein. Representative sulfamyl groups are aminosulfamoyl (H2NSO2xe2x80x94) and dimethylaminosulfamoyl (Me2NSO2xe2x80x94).
The preparation of the fluorophenyl resin compound of formula 
wherein A is xe2x80x94YC(O)xe2x80x94 and B is xe2x80x94OH is shown in Scheme 1. 
According to the foregoing Scheme 1, amino resin 1 or hydroxy resin 4 is coupled with the 4-hydroxyfluorobenzoic acid derivative 2 in a suitable organic solvent such as dichloromethane, DMF, DMSO or THF to form the 4-hydroxyfluorobenzamido resin compound 3 or 4-hydroxyfluorobenzoyloxy resin compound 5. Coupling times range from about 2 to about 24 hours, depending upon the amino resin and 4-hydroxyfluorobenzoic acid derivative to be coupled, activating agent, solvent and temperature. The coupling is accomplished at from about xe2x88x9210xc2x0 C. to about 50xc2x0 C., preferably at about ambient temperature. The carboxylic acid moiety is activated with an appropriate activating agent (for a list of activating agents, with specific references, see Arrieta et al., Synn. Commun. 13, 471, 1983) such as isopropyl chloroformate in the presence of N-methylmorpholine, diisopropylcarbodiimide (DIC) in the presence of 1-hydroxybenzotriazole (HOBT), diisopropylcarbodiimide (DIC) in the presence of 4-dimethylaminopyridine. (DMAP), bis(2-oxo-3-oxazolidinyl)-phosphonic chloride (BOP-Cl) in the presence of triethylamine, bromotripyrrolidinophosphonium hexafluorophosphate (PyBrop(trademark)) in the presence of triethylamine (TEA), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in the presence of diisopropylethyl amine, N-hydroxysuccinimide in the presence of N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC), pyridinium salts-Bu3N, phenyl dichlorophosphate PhOPOCl2, 2-chloro-1,3,5-trinitrobenzene and pyridine, polyphosphate ester, chlorosulfonyl isocyanate ClSO2NCO, chlorosilane, MeSO2Cl-Et3N, PH3Pxe2x80x94CCl4-Et3N, and the like.
A preferred amino resin 1 for preparing the 4-hydroxyfluorobenzamido resins of this invention is aminomethyl polystyrene. Depending on the size of the particles, (200 or 400 mesh), aminomethyl polystyrene has loading ranges of from about 0.5 to about 1.2 mmol/g and from about 0.1 to about 0.5 mmol/g, respectively.
A preferred hydroxy resin 4 is hydroxymethyl resin.
In a preferred method of preparing the 4-hydroxyfluorobenzamido resin 3, a mixture of the 4-hydroxyfluorobenzoic acid derivative 2, aminomethyl polystyrene, diisopropylcarbodiimide (DIC) and 4-dimethylaminopyridine (DMAP) in anhydrous DMF is stirred at about ambient temperature for about 18 hours. The 4-hydroxyfluorobenzamido resin 3 is then filtered, washed with one or more solvents and dried.
The preparation of the fluorophenyl resin compound of formula 
wherein A is 
D is CH or N; R0, R1, and R2 are as defined herein; P is 0, 1, or 2; and B is OH is shown in Scheme 2. 
As shown in the Scheme 2 above, coupling of the azacycloalkyl resin compound 6 with the 4-hydroxyfluorobenzoic acid compound 2 provides the 4-hydroxyfluorobenzoyl-azacycloalkyl resin compound 7. The coupling is accomplished using the reagents and conditions described in Scheme 1 above. A preferred azacycloalkyl resin compound is (piperidinomethyl) polystyrene, designated herein as 
(piperidinormethyl) polystyrene
The preparation of the fluorophenyl resin compound of formula 
wherein A is 
and B is F, OH, SO3H or SO2Cl is shown in Scheme 3. 
As shown in Scheme 3, Friedel-Crafts acylation of polystyrene with the 4-fluorofluorobenzoyl chloride derivative 8, in the presence of a Lewis acid such as FeCl3, SnCl4 or AlCl3 in a suitable organic solvent provides the 4-fluorofluorobenzoyl resin compound 9. Reaction of 9 with hydroxide provides the 4-hydroxyfluorobenzoyl resin compound 10.
In a preferred aspect, polystyrene is acylated with the 4-fluorobenzoyl chloride derivative 8 in the presence of AlCl3 in nitrobenzene to provide the 4-fluorobenzoyl resin compound 9. A mixture of 9 in water/cyclohexane is treated with sodium hydroxide and tetrabutylammonium hydrogen sulfate according to the procedure of Feldman et al., J. Org. Chem., 56 (26), 7350-7354 (1991), to provide the 4-hydroxypolyfluorobenzoyl resin compound 10.
Reaction of the fluorobenzoyl resin compound 9 with an SO3xe2x88x92 equivalent such as potassium metabisulfite in the presence of base in a suitable organic solvent such as dichloromethane, dichloroethane or chloroform provides the fluorobenzoyl-4-sulfonic acid resin compound 11. Representative bases include diisopropylethylamine, pyridine, triethylamine, N-methylpiperidine, and the like. Reaction of the fluorobenzoyl-4-sulfonic acid resin compound 11 with an acid chloride including chlorosulfonic acid, thionyl chloride, oxalyl chloride, and the like, in an inert organic solvent provides the 5,6-trifluorobenzoyl-4-sulfonyl chloride acid resin compound 12.
The preparation of the fluorophenyl resin compound of formula 
wherein A is xe2x80x94NR3SO2xe2x80x94 and B is F or OH is outlined in Scheme 4. 
As shown in Scheme 4, reaction of amino resin 1 with the 4-hydroxyfluorophenylsulfonyl chloride compound 13 in the presence of base such as N-methylmorpholine, pyridine, collidine, triethylamine or diisopropylethylamine in a suitable organic solvent such as dichloromethane, dichloroethane, dioxane, THF or DMF, provides the 4-hydroxyfluorophenylsulfonamide resin compound 14. The reaction is preferably conducted in dichloromethane in the presence of collidine.
Alternatively, amino resin 1 is reacted with the 4-fluorofluorophenylsulfonyl chloride compound 15 as described above to give the 4-fluorofluorophenylsulfonamide resin compound 16 which is converted to the desired 4-hydroxyfluorophenylsulfonamide resin compound 14 under reaction conditions analogous to those described for the conversion of 9 to 10, as described in Scheme 3 above.
The preparation of the fluorophenyl resin compound of formula 
wherein A is xe2x80x94C6H4xe2x80x94 and B is F, OH, SO3H or SO2Cl is shown in Scheme 5. 
As shown in Scheme 5, bromination of polystyrene, for example using Br2 in the presence of FeCl3, TI(OAc)3 or BF3 gives the brominated polystyrene resin compound 17. Metal halogen exchange, for example using an alkyllithium reagent such as n-butyllithium in benzene or TMEDA; addition of trimethylborate; and acidic workup provides the polystyryl boronic acid resin compound 18. Coupling of compound 18 with the fluorophenyl halide compound 19 using Suzuki conditions (catalytic Pd(0), basic conditions; See Frenette et al., Tetrahedron Lett., 1994, 35, 9177 and Brown et al., J. Amer. Chem. Soc., 1996, 118, 6331) provides the 4-fluorofluorophenyl polystyrene resin compound 20. Conversion of 20 to the 4-hydroxyfluorophenyl polystyrene resin compound 21, fluorophenyl-4-sulfonic acid polystyrene resin compound 22 or the fluorophenyl-4-sulfonyl chloride polystyrene resin compound 23 is accomplished under reaction conditions analogous to those described in Scheme 3 above.
The preparation of the fluorophenyl resin compound of formula 
wherein A is xe2x80x94C6H4xe2x80x94SO2 and B is F or OH is outlined in Scheme 6 which describes the preparation of 4-hydroxy-polyfluorophenylsulfonyl-polystyrene resin. It is understood that the methodology described below may be readily adapted to the preparation of additional 4-hydroxyfluorophenylsulfonyl resin compounds. 
As shown in the foregoing Scheme 6, reaction of thiopolystyrene with hexafluorobenzene results in formation of the polyfluorophenylthio-polystyrene resin compound 24. The reaction is preferably carried out in a suitable solvent such as toluene, dioxane, DMF or DMSO, in the presence of base, preferably catalytic pyridine or N-methylmorpholine. Conversion of 24 to the 4-hydroxy-polyfluorophenylthio-polystyrene resin compound 25 is accomplished as described in Scheme 3 above. Oxidation of 25, for example using m-chloroperbenzoic acid (MCPBA) provides of 4-hydroxy-polyfluorophenylsulfonyl-polystyrene resin 26.
Preferred fluorophenyl resin compounds of this invention have formula I wherein R0, R1 and R2 are independently nitro, monohaloalkyl, dihaloalkyl, trihaloalkyl (e.g., CF3), bromo, chloro, fluoro, cyano, alkoxy, formyl, lower alkanoyl, lower alkylsulfonyl, lower alkylsulfinyl, and the like. Preferably, fluoro.
Preferred fluorophenyl resin compounds of this invention have formula I wherein R0, R1 and R2 are F; R4, R5, R6 and R7 are H; and B is OH, SO3H or SO2Cl.
Representative preferred fluorophenyl resin compounds include, but are not limited to:
4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl-polystyrene resin, designated herein as 
4-(N,Nxe2x80x2-diisopropyl-isourea)-2,3,5,6-tetrafluorobenzamidomethyl-copoly(styrene-1%-divinylbenzene)-resin, designated herein as 
4-(tripyrolidinium-O-phosphonium)-2,3,5,6-tetrafluorobenzamidomethyl-copoly(styrene-1%-divinylbenzene)-resin, designated herein as 
2,3,5,6-tetrafluorobenzamidomethyl-4-sulfonic acid-polystyrene resin, designated herein as 
2,3,5,6-tetrafluorobenzamidomethyl-4-sulfonyl chloride-polystyrene resin, designated herein as 
4-hydroxy-2,3,5,6-tetrafluornbenzoyloxymethyl-polystyrene resin, designated herein as 
2,3,5,6-tetrafluorobenzoyloxymethyl-4-sulfonic acid-polystyrene resin, designated herein as 
2,3,5,6-tetrafluorobenzoyloxymethyl-4-sulfonyl chloride-polystyrene resin, designated herein as 
4-hydroxy-2,3,5,6-tetrafluorobenzoyl-polystyrene resin, designated herein as 
2,3,5,6-tetrafluorobenzoyl-4-sulfonic acid-polystyrene resin, designated herein as 
2,3,5,6-tetrafluorobenzoyl-4-sulfonyl chloride-polystyrene resin, designated herein as 
4-hydroxy-2,3,5,6-tetrafluorophenylsulfonamidomethyl-polystyrene resin, designated herein as 
2,3,5,6-tetrafluorophenylsulfonamidomethyl-4-sulfonic acid-polystyrene resin, designated herein as 
2,3,5,6-tetrafluorophenylsulfonamidomethyl-4-sulfonyl chloride-polystyrene resin, designated herein as 
N-(4-hydroxy-2,3,5,6-tetrafluorobenzoyl)-piperidinomethyl-polystyrene resin, designated herein as 
N-(2,3,5,6-tetrafluorobenzoyl-4-sulfonic acid)-piperidinomethyl-polystyrene resin, designated herein as 
N-(2,3,5,6-tetrafluorobenzoyl-4-sulfonyl chloride)-piperidinomethyl-4-polystyrene resin, designated herein as 
N-(4-hydroxy-2,3,5,6-tetrafluorophenylsulfonyl)-piperidinomethyl-polystyrene resin, designated herein as 
N-((2,3,5,6-tetrafluorophenyl-4-sulfonic acid)sulfonyl)-piperidinomethyl-polystyrene resin, designated herein as 
N-((2,3,5,6-tetrafluorophenyl-4-sulfonyl chloride)sulfonyl)-piperidinomethyl-polystyrene resin, designated herein as 
4-hydroxy-2,3,5,6-tetrafluorophenyl-polystyrene resin, designated herein as 
2,3,5,6-tetrafluorophenyl-4-sulfonic acid-polystyrene resin, designated herein as 
2,3,5,6-tetrafluorophenyl-4-sulfonyl chloride polystyrene resin, designated herein as 
4-hydroxy-2,3,5,6-tetrafluorophenylsulfonyl-polystyrene resin, designated herein as 
2,3,5,6-tetrafluorophenylsulfonyl-4-sulfonic acid-polystyrene resin, designated herein as 
2,3,5,6-tetrafluorophenylsulfonyl-4-sulfonyl chloride-polystyrene resin, designated herein as 
More preferred fluorophenyl resin compounds have formula I wherein
A is selected from 
L is a chemical bond, 
According to the foregoing Scheme 7, carboxylic acid compound 27 is coupled to the fluorophenyl resin compound IA using coupling conditions analogous to those described in Scheme 1 above to form the fluorophenyl activated ester resin compound II. Coupling times range from about 2 to about 24 hours depending on the nature of the fluorophenyl resin compound I, carboxylic acid 27, solvent, reaction temperature and activating agent. Coupling is preferably accomplished using diisopropylcarbodiimide (DIC) optionally in the presence of catalytic 4-dimethylaminopyridine (DMAP), or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP(trademark)) in the presence of triethylamine (TEA). The coupling reaction being carried out in a suitable solvent such as benzene, dichloromethane, dichloroethane, dioxane, THF or DMF at about ambient temperature over about 18 hours. A preferred solvent is anhydrous DMF. The fluorophenyl activated ester resin compound II is then washed with a suitable organic solvent or solvents to remove excess reagents. The fluorophenyl activated ester resin compound II may be dried and stored for future use or used directly in subsequent reactions.
The fluorophenyl activated ester resin compound II is odorless, air stable and free flowing. It is stable to storage at ambient temperature, and may be handled without any special precautions. A slurry of the fluorophenyl activated ester resin compound II in a solvent mixture such as DMF: dichloromethane may be used to distribute the resin via pipette, thereby facilitating automation. In contrast many acid chlorides and sulfonyl chlorides decompose under similar conditions, and are usually unstable to moisture in the air.
The cleavage of the fluorophenyl activated ester resin compound II with an amine is shown in Scheme 8. In Scheme 8, Rb and Rc represent independently H, an aliphatic group or an aromatic group, or Rb and Rc, together with the N-atom to which they are attached form an optionally substituted azacycloalkyl ring or azacycloalkenyl ring, wherein Rb and Rc are amenable to the reaction of the amine 28 with the carbonyl moiety of the fluorophenyl activated ester resin compound II to effect the cleavage reaction described below using the reaction conditions described herein,
Scheme 8
m is 1 to 5;
Y is NR3 or NR3SO2;
B is xe2x80x94OH, xe2x80x94SO3H, or xe2x80x94SO2Cl; and
R3 is H.
Representative more preferred fluorophenyl resin compounds include, but are not limited to
4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl-polystyrene resin,
2,3,5,6-tetrafluorobenzamidomethyl-4-sulfonic acid-polystyrene resin,
2,3,5,6-tetrafluorobenzamidomethyl-4-sulfonyl chloride-polystyrene resin,
4-hydroxy-2,3,5,6-tetrafluorobenzoyl-polystyrene resin,
2,3,5,6-tetrafluorobenzoyl-4-sulfonic acid-polystyrene resin,
2,3,5,6-tetrafluorobenzoyl-4-sulfonyl chloride-polystyrene resin,
4-hydroxy-2,3 ,5,6-tetrafluorophenylsulfonamidomethyl-polystyrene resin,
4-(tripyrolidinium-O-phosphonium)-2,3,5,6-tetrafluorobenzamidomethyl-copoly(styrene-1%-divinylbenzene)-resin,
4-(N,Nxe2x80x2-diisopropyl-isourea)-2,3,5,6-tetrafluorobenzamidomethyl-copoly(styrene-1%-divinylbenzene)-resin
2,3,5,6-tetrafluorophenylsulfonamidomethyl-4-sulfonic acid-polystyrene resin and
2,3,5,6-tetrafluorophenylsulfonamidomethyl-4-sulfonyl chloride-polystyrene resin.
The preparation of fluorophenyl activated ester resin compounds using the fluorophenyl resin compounds of this invention is shown in Scheme 7. In Scheme 7, Ra represents any aliphatic or aromatic group amenable to coupling of the carboxylic acid compound 27 with the fluorophenyl resin compound IA using the reaction conditions described herein. The group Ra may be further substituted and may contain functional groups suitable for further chemical transformations while attached to the resin. It is understood that these functional groups may be suitably protected to prevent interference with the coupling reaction and subsequent cleavage reaction described below. For a comprehensive treatise on the protection and deprotection of common functional groups see T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), incorporated herein by reference. 
As shown in Scheme 8, the fluorophenyl activated ester resin compound II is cleaved by reaction with an amine of formula HNRbRc in an organic solvent such as dichloromethane, dichloroethane, dioxane, THF or DMF at from about 20xc2x0 C. to about 60xc2x0 C. to prepare the amide 29. The reaction temperature and amount of time required for the cleavage reaction depends on the nature of the substituents Rb and Rc. Cleavage is generally accomplished at about ambient temperature over about 2 to about 48 hours. A catalyst such as 4-dimethylaminopyridine is optionally added to accelerate the cleavage reaction.
In a similar manner, the fluorophenyl activated ester resin compound II is cleaved by reaction with a hydroxylamine of formula H2NOP wherein P is a hydroxy protecting group, preferably tetrahydropyranyl (THP). Removal of the hydroxy protecting group, for example using trifluoroacetic acid/dichloromethane when P is THP, provides the hydroxamic acid 31.
The reactivity of the fluorophenyl activated ester resin compound II toward cleavage by amines is comparable to the reactivity of the corresponding unsupported acylating reagent. Many amines possessing varying reactivities, including deactivated anilines such as 4-nitroaniline, react with the fluorophenyl activated ester resin compound II to give amide products. Typically less than one equivalent of the nucleophile is required to afford quantitative acylation of the nucleophile.
Polyfluorophenyl activated ester resin compounds possess further advantages over unsupported activated esters (i.e. pentafluorophenol, 4-nitrophenol) as well as acylating agents such as acid chlorides or acid anhydrides, including product isolation comprising simple filtration and solvent evaporation. There is no salt by-product or phenol by-product. The proton generated during the cleavage reaction is scavenged by the resin-bound fluorophenolate anion, therefore, in general, no excess base is required.
The fluorophenyl resin compounds of this invention are also useful for the preparation of peptides. In general, this method involves coupling the carboxyl group of a suitably N-protected first amino acid to the resin to form the resin-bound N-protected fluorophenyl activated ester resin compound, followed by cleavage of the fluorophenyl activated ester resin compound with a carboxy protected second amino acid to form a dipeptide which is protected at the carboxy and N termini.
If desired, a third amino acid is added by removing the N-protection from the dipeptide prepared as described above to form the carboxy protected dipeptide and cleaving the fluorophenyl activated ester resin compound of the third amino acid (suitably N-protected) to form the tripeptide which is protected at the carboxy and N termini. This process is then repeated until the desired amino acid residues have been incorporated in the peptide.
Alternatively, peptides comprising multiple amino acids are prepared by coupling a suitably N-protected peptide subunit comprising two or more amino acids to the fluorophenyl resin compound to form the fluorophenyl activated ester resin compound, and cleaving the fluorophenyl activated ester resin compound with a carboxy protected amino acid or second peptide subunit. Thus, in addition to the sequential addition of amino acids described above, a polypeptide may be prepared using the fluorophenyl resin compounds of this invention by coupling a N-protected peptide to the resin and cleaving the N-protected peptide fluorophenyl activated ester resin compound with a carboxy protected amino acid or peptide, or by coupling a N-protected amino acid to the resin and cleaving the N-protected amino acid fluorophenyl activated ester resin compound with a carboxy protected peptide.
N-protecting groups suitable for use in peptide synthesis using the fluorophenyl resin compounds of this invention should have the properties of being stable to the conditions of coupling to the amino acid or peptide to the fluorophenyl resin compound and cleavage of the fluorophenyl activated ester resin compound, while being readily removable without destruction of the growing peptide chain or racemization of any of the chiral centers contained therein. Suitable protecting groups include 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), biphenylisopropyloxycarbonyl, t-amyloxycarbonyl, isobomyloxycarbonyl, (xcex1,xcex1)dimethyl-3,5-dimethoxybenzyloxycarbonyl, o-nitrophenylsulfenyl, 2-cyano-t-butyloxycarbonyl, and the like.
Carboxy protecting groups suitable for use in peptide synthesis using the fluorophenyl resin compounds of this invention should have the properties of being stable to cleavage of the resin-bound fluorophenyl activated ester, while being readily removable without destruction of the growing peptide chain or racemization of any of the chiral centers contained therein. Examples of carboxy protecting groups include esters such as methoxymethyl, methylthiomethyl, tetrahydropyranyl, benzyloxymethyl, substituted and unsubstituted phenacyl, 2,2,2-trichloroethyl, tert-butyl, cinnamyl, substituted and unsubstituted benzyl, trimethylsilyl, allyl, and the like, and amides and hydrazides including N,N-dimethyl, 7-nitroindolyl, hydrazide, N-phenylhydrazide, and the like. Especially preferred carboxylic acid protecting groups are tert-butyl and benzyl.
The fluorophenyl resin compounds of this invention are also useful for the preparation of amines as outlined in Schemes 9a and 9b. In scheme 9a, A, R0, R1, R2, Ra, Rb and Rc are as defined herein. 
As shown in Scheme 9a, the 4-(oxysulfonyl)fluorophenyl resin compound 33 is prepared by reacting the fluorophenyl-4-sulfonyl chloride resin compound III with the hydroxy compound RaOH 32. The reaction is preferably carried out at ambient temperature in a suitable organic solvent such as dichloromethane, dichloroethane, dioxane, THF or DMF, in the presence of a base such as N-methylmorpholine, pyridine, collidine, triethylamine or diisopropylethylamine. Reaction of the 4-(oxysulfonyl)fluorophenyl resin compound 33 with the amine 28 provides the amine 34.
An alternative preparation of amines using the fluorophenyl resin compound of this invention is shown in Scheme 9b. In Scheme 9b, A, R0, R1, R2, and Ra is as defined herein and Ri represents a group of formula xe2x80x94CH2Rf wherein Rf is an aliphatic or aromatic group amenable to reaction with the N-substituted fluorophenyl-4-sulfonamido resin compound 36 to form the N,N-disubstituted fluorophenyl-4-sulfonamido resin compound 39, and reaction of39 with a thiol, using the reaction conditions described below. 
As shown in Scheme 9b, reaction of the fluorophenyl-4-sulfonyl chloride resin compound III with the primary amine 35 in a suitable organic solvent such as dichloromethane, dichloroethane, dioxane, THF or DMF, in the presence of a base such as N-methylmorpholine, pyridine, collidine, triethylamine or diisopropylethylamine provides the N-substituted fluorophenyl-4-sulfonamido resin compound 36. Reaction of 36 with an alkylating agent of formula RiX wherein X is Br or Cl, in a suitable organic solvent such as THF or DMF, in the presence of a base such as triethylamine or cesium carbonate; or with an alcohol of formula RiOH using Mitsunobu conditions (diethylazodicarboxylate or diisopropylazodicarboxylate and triphenylphosphine or tributylphosphine) provides the N,N-disubstituted fluorophenyl-4-sulfonamido resin compound 39. The secondary amine 40 is then displaced by treatment of the N,N-disubstituted fluorophenyl-4-sulfonamido resin compound 39 with a thiol compound such as thiophenol or ethanethiol.
The fluorophenyl resin compounds of this invention are also useful for the preparation of sulfonamides wherein Ra, Rb and Rc are as defined herein is outlined in Scheme 10. 
As shown in Scheme 10, reaction of the fluorophenyl resin compound IA with the sulfonyl chloride compound 41 or the sulfonic anhydride 42 results in formation of the 4-(sulfonyloxy)fluorophenyl resin compound 44. The reaction is preferably conducted at about ambient temperature in a suitable organic solvent such as dichloromethane, dichloroethane, dioxane, THF or DMF in the presence of a base such as N-methylmorpholine, pyridine, collidine, triethylamine or diisopropylethylamine. The 4-(sulfonyloxy)fluorophenyl resin compound 44 is also prepared by coupling of IA with the sulfonic acid compound 43, using analogous reagents and reaction conditions as described in Scheme 7, above. A preferred activating agent is diisopropylcarbodiimide.(DIC). Reaction of the 4-(sulfonyloxy)fluorophenyl resin compound 44 with the amine 28 in a suitable organic solvent as described above, preferably a polar aprotic solvent such as DMF, results in formation of the sulfonamide 45.
The preparation of carbamates 47 and urethanes 48 using the fluorophenyl resin compound of this invention is outlined in Scheme 11. In Scheme 11, Ra, Rb and Rc are defined herein and Rd and Re represent independently H, an aliphatic group or an aromatic group amenable, or Rd and Re, together with the N-atom to which they are attached form an optionally substituted azacycloalkyl ring or azacycloalkenyl ring, wherein Rd and Re are amenable to the reaction conditions described herein for cleavage of the 4-(aminocarbonyloxy)fluorophenyl resin compound 46. 
As shown in Scheme 11, reaction of the 4-(aminocarbonyloxy)fluorophenyl resin compound 46 with the hydroxy compound RaOH in a suitable organic solvent such as dichloromethane, dichloroethane, dioxane, THF or DMF, in the presence of a base such as N-methylmorpholine, pyridine, collidine, triethylamine or diisopropylethylamine results in formation of the carbamate 47.
Likewise, reaction of 46 with an amine of formula HNRdRe in a suitable organic solvent such as dichloromethane, dichloroethane, dioxane, THF or DMF, in the presence of a base such as N-methylmorpholine, pyridine, collidine, triethylamine or diisopropylethylamine results in formation of the urethane 48.
The 4-(aminocarbonyloxy)fluorophenyl resin compound 46 is prepared by reaction of the fluorophenyl resin compound IA with phosgene or 1,1xe2x80x2-carbonyldiimidazole in a suitable organic solvent such as dichloromethane, dichloroethane, dioxane, THF or DMF, optionally in the presence of a base such as N-methylmorpholine, pyridine, collidine, triethylamine or diisopropylethylamine, results in formation of the (4-carbonyloxy)fluorophenyl resin compound 49. Reaction of 49 with the amine of formula HNRbRc in a suitable organic solvent and base as described above gives the 4-(aminocarbonyloxy)fluorophenyl resin compound 46.
The 4-(aminocarbonyloxy)fluorophenyl resin compound 46 may also be prepared in a single step by reaction of the fluorophenyl resin compound IA with a carbamoyl chloride of formula ClC(O)NRbRc. The reaction is performed in a suitable organic solvent such as dichloromethane, dichloroethane, dioxane, THF or DMF, in the presence of a base such as N-methylmorpholine, pyridine, collidine, triethylamine or diisopropylethylamine. In cases in which one of Rb and Rc is H and the other is aliphatic or aromatic, the 4-(aminocarbonyloxy)fluorophenyl resin compound 46 may be prepared by reaction of I with the isocyanate of formula Oxe2x95x90Cxe2x95x90Nxe2x80x94Rb or Oxe2x95x90Cxe2x95x90Nxe2x80x94Rc in a suitable organic solvent optionally in the presence of a base as described above
The use of the fluorophenyl resin compound of this invention for the preparation of carbonates and in an alternative route to carbamates is shown in Scheme 12. In Scheme 12, Ra, Rb, Rc and Rf are as defined herein. 
As shown in Scheme 12, reaction of the fluorophenyl resin compound IA with a chloroformate of formula ClC(Q)ORa in a suitable organic solvent such as dichloromethane, dichloroethane, dioxane, THF or DMF, optionally in the presence of a base such as N-methylmorpholine, pyridine, collidine, triethylamine or diisopropylethylamine provides the 4-(oxycarbonyloxy)fluorophenyl resin compound 49. Reaction of 49 with the amine HNRbRc as described in Scheme 11 results in formation of the carbamate 47.
Likewise, reaction of 49 with an alcohol of formula RfOH in a suitable organic solvent such as dichloromethane, dichloroethane, dioxane, THF or DMF, optionally in the presence of a base such as N-methylmorpholine, pyridine, collidine, triethylamine or diisopropylethylamine provides the carbonate 50.
Additionally, the fluorophenyl resin compounds of this invention are useful for constructing arrays of amide, peptide, hydroxamic acid, amine or sulfonamide combinatorial libraries or arrays of amides, peptides, hydroxamic acids, amines or sulfonamides as reagents in combinatorial library synthesis, for example reagents for the Ugi 4-component condensation (Ivar Ugi, in Isonitrile Chemistry, 1971, p. 145, Academic Press). The fluorophenyl resin compounds of this invention may be used for single functional group transformations and multiple step solid phase synthesis to generate combinatorial libraries.
The cleavage of the fluorophenyl activated ester resin compound II with carbon nucleophiles is shown in Scheme 13. In Scheme 13, Ra is as defined herein and the groups Rg and Rh are independently H or any aliphatic or aromatic group which alone or in combination with the other of Rg and Rh renders the xcex1-hydrogen sufficiently acidic to permit preparation of the carbon nucleophile xe2x80x94CHRgRh under the basic reaction conditions described herein. Rg and Rh may contain additional functional groups. It is understood that these functional groups may be suitably protected to prevent interference with the deprotonation and cleavage reactions described below. For a comprehensive treatise on the protection and deprotection of common functional groups see T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), incorporated herein by reference. 
As shown in Scheme 13 above, treatment of the xcex1-acidic carbon compound H2CRgRh 51 or halocarbon HXRgRh (52, X=halogen) with base such as triethylamine, diisopropylethylamine, K2CO3, NaH, LiH, KH, lithium diisopropylamide, lithium hexamethyidisilazide, and the like, results in formation of the carbon nucleophile RgRhCHxe2x8ax96M⊕ 53, wherein M⊕ represents a metal cation such as K+, Na+ or Li+ or a quaternary nitrogen species resulting from extraction of a proton with an amine base such as triethylamine or diisopropylethylamine. The carbon nucleophile 53 may also be prepared by metal-halogen exchange, for example using magnesium metal to form the Grignard reagent, in which case M⊕ is MgBr. The reaction is carried out in an inert organic solvent such as tetrahydrofuran, diethyl ether, dioxane or dimethoxyethane at a temperature of from about xe2x88x9278 C to about ambient temperature. Reaction of 53 with the fluorophenyl activated ester resin compound II results in formation of the xcex1-substituted carbonyl compound 54.
Alternatively, the carbon nucleophile 53 may be generated using a polymeric base such as the polymeric trityllithium reagent described by Cohen et al., J. Amer. Chem. Soc., 1977, 99, 4165.
Preferred xcex1-acidic carbon compounds suitable for use as carbon nucleophiles include Meldrum""s acid, benzyl cyanide, acetophenone, ethyl phenylacetate, ethyl acetoacetate, triethyl phosphonoacetate and (carbethoxymethylene)triphenylphosphorane, Most preferred carbon nucleophile is a lithium enolate of a ketone, e.g. a lithium enolate of acetophenone, as exemplified in example 7.
The use of the fluorophenyl resin compounds of this invention for the parallel synthesis of a multiplicity of different amide, peptide, hydroxamid acid, amine, carbamate, urethane or sulfonamide end products is illustrated by the preparation of a multiplicity of amides shown in Schemes 14a and 14b below. In Schemes 14a and 14b, Ra Rb and Rc are as defined herein and n is an integer which represents the total number of different amide products being prepared. 
The parallel synthesis of a multiplicity of amides using a multiplicity of carboxylic acid compounds RalCO2H to RanCO2H and a single amine HNRbRc is shown in Scheme 14a. According to Scheme 14a, the fluorophenyl resin of this invention is divided into n portions. Each portion of resin is then coupled with a different carboxylic acid compound to give n portions of fluorophenyl activated ester resin compound. Each portion of fluorophenyl activated ester resin compound is then cleaved with an amine of formula HNRbRc to give n portions of amide derived from a single amine but having different carbonyl group substituents. 
The parallel synthesis of n amides having variable N-substituents Rcl to Rcn is outlined in Scheme 14b above. According to Scheme 14b, the fluorophenyl resin compound of this invention is coupled with a carboxylic acid of formula RaCO2H. The resulting fluorophenyl activated ester resin compound is then divided into n portions, and each portion of fluorophenyl activated ester resin compound is cleaved with a different amine HNRbRcl to 1NRbRcn to give the n different amide compounds derived from a single carboxylic acid.
The fluorophenyl resin compounds of this invention are also useful for constructing a combinatorial library of amide, peptide, hydroxamic acid, amine or sulfonamide end products as illustrated for the simple amide library prepared from 4 carboxylic acids and 4 amines outlined in Scheme 15. 
As shown in the foregoing Scheme 15, the fluorophenyl resin compound is divided in 4 portions, and each portion is coupled with a different carboxylic acid compound to prepare 4 different fluorophenyl activated ester resin compounds. The fluorophenyl activated ester resin compounds are then mixed together to form a single portion which is divided into 4 portions of fluorophenyl activated ester resin compound, in which each portion contains approximately equal amounts of each individual fluorophenyl activated ester resin compound. Each of the 4 portions of fluorophenyl activated ester resin compound is then cleaved with a different amine to give 4 portions of amide, each of which contains 4 compounds representing the products of cleavage of the 4 different fluorophenyl activated ester resin compound with a single amine. In this manner a combinatorial library containing a multiplicity of amides may be quickly constructed. In a similar manner, a combinatorial library of peptides may be assembled by repeating the dividing-recombining sequence for each amino acid or peptide building block.
The methodology described above for solid phase synthesis on resins is readily extended to synthesis on pins wherein the pins comprise a detachable polyethylene- or polypropylene-base head and an inert stem. The heads are grafted with a functionalized methacrylate copolymer on which the synthesis takes place. Synthesis on pins offers several advantages over resin-based solid phase synthesis techniques because it readily lends itself to automation and reduces the handling difficulties associated with conventional resin-based solid phase synthesis. Synthesis on pins is especially useful for the rapid construction of combinatorial libraries of amides or peptides. Solid phase synthesis pins is described in Technical Manual, Multipin(trademark) SPOC, Chiron Technologies (1995) and references therein.
The preparation of amides on amino-functionalized pins is outlined in Scheme 16. In Scheme 16, 
represents the polyethylene or polypropylene head described above on which is grafted a methacrylic acid-dimethylacrylamide copolymer substituted with a plurality of amino groups. The Fmoc-protected functionalized pin 55 is available from Chiron Mimotopes, San Diego, Calif. It is understood that while the preparation of amides is exemplified below, the methodology described in Schemes 1-14 above for the resin compounds of this invention is equally applicable to pins. 
According to the foregoing Scheme 16, the Fmoc protected amino polymer 55 is deprotected by treatment with a basic amine, preferably 20% piperidine/DMF or 2% DBU/DMF. The free amino polymer 56 is functionalized by coupling with the 4-hydroxyfluorocarboxylic acid compound 2, for example using 1-hydroxybenzotriazole (HOBT) in the presence of N-methylmorpholine (NMM), diisopropylcarbodiimide (DIC) in the presence of HOBT or dicyclohexylcarbodiimide (DCC) in the presence of HOBT in a suitable solvent such as dichloromethane, N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), or dichloromethane/DMF mixtures, to prepare the functionalized pins 57. Coupling of 57 with the carboxylic acid compound 27 to form the polymer bound fluorophenyl activated ester 58, followed by cleavage of 58 with the amine 28 provides the amide 29 under reaction conditions analogous to those described in Schemes 7 and 8 above.
It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.
The foregoing may be better understood by reference to the following examples, which are presented for illustration and are not intended to limit the scope of this invention.
19F NMR spectra were obtained on a Varian unityplus spectrometer operating at a 1H frequency of 500 MHz. The 1H nanoprobe was tuned to 19F frequency. Typically, spectra were acquired with a (delay-pulse-acquire) sequence repeated for a number of transients (nt). Typical spectral width was 100,000 Hz and the chemical shifts were referenced relative to CFCl3 using the transmitter frequency. The spectra were acquired using a nanoprobe in which the sample was oriented at a gmagic angle (54.7 degrees) relative to the magnetic field and the sample was spun at a rate of 1000-1500 Hz. The samples were prepared by swelling 1-2 mgs of resin with about 40 ul of deuterated dimethylformamide (DMF).